ORGANIC LETTERS
Efficient Synthesis of the C1−C11 Fragment of the Tedanolides. The Nonaldol Aldol Process in Synthesis
2000 Vol. 2, No. 12 1669-1672
Michael E. Jung* and Rodolfo Marquez Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
[email protected] Received February 15, 2000
ABSTRACT
The nonaldol aldol process developed in our laboratories has been applied to the synthesis of a C1−C11 fragment 22 of the novel macrocyclic cytotoxic agents tedanolide and 13-deoxytedanolide 1 and 2. The commercially available hydroxy ester 7 was converted in 24 steps into compound 22 using two nonaldol aldol reactions.
Since their isolation and characterization1,2 in the mid 1980s and early 1990s, the cytotoxic marine macrocycles tedanolide 1 and 13-deoxytedanolide 2 have attracted a great deal of synthetic interest due to their strong biological activity and structural complexity.3 Tedanolide 1 has shown ED50’s of 250 pg/mL (vs the KB human carcinoma cell line) and 16 pg/mL (vs PS lymphocytic leukemia). Preliminary data also suggest that tedanolide 1 may induce terminal cell dif(1) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.; van der Helm, D. J. Am. Chem. Soc. 1984, 106, 7251. (2) Fusetani, N.; Sugawara, T.; Matsunaga, S.; Hirota, H. J. Org. Chem. 1991, 56, 4971. (3) (a) Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron Lett. 1996, 37, 385. (b) Matsushima, T.; Mori, M.; Nakajima, N.; Maeda, H.; Uenishi, J.; Yonemitsu, O. Chem. Phar. Bull. 1998, 46, 1335. (c) Liu, J. F.; Abiko, A.; Pei, Z.-H.; Buske, D. C.; Masamune, S. Tetrahedron Lett. 1998, 39, 1873. (d) Taylor, R. E.; Ciavarri, J. P.; Hearn, B. R. Tetrahedron Lett. 1998, 39, 9361. (e) Matsushima, T.; Mori, M.; Zheng, B. Z.; Maeda, H.; Nakajima, N.; Uenishi, J.; Yonemitsu, O. Chem. Phar. Bull. 1999, 47, 308. (f) Zheng, B. Z.; Maeda, H.; Mori, M.; Kusaka, S.; Yonemitsu, O.; Matsushima, T.; Nakajima, N.; Uenishi, J. Chem. Phar. Bull. 1999, 47, 1288. (g) Matsushima, T.; Zheng, B. Z.; Maeda, H.; Nakajima, N.; Uenishi, J.; Yonemitsu, O. Synlett 1999, 780. (h) Roush, W. R.; Lane, G. C. Org. Lett. 1999, 1, 95. (i) Smith, A. B., Lodise, S. A. Abstracts of Papers, 218th National Meeting of the American Chemical Society, New Orleans, LA, Aug 22-26, 1999; Amercian Chemical Society: Washington, DC, 1999; p 549. Org. Lett. 1999, 1, 1249. 10.1021/ol005675l CCC: $19.00 Published on Web 05/19/2000
© 2000 American Chemical Society
ferentiation at the S phase at concentrations as low as 10 ng/mL, which offers the possibility of using it as a mechanism-based drug lead. 13-Deoxytedanolide 2, on the other hand, has shown a T/C of 189% at a dose of 125 µg/kg vs p388 cell lines.1,2 No mechanistic studies have been published for 13-deoxytedanolide 2 to date. Structurally, both macrocycles are composed of an 18membered macrocyclic lactone with a polypropionate skeleton, an internal trisubstituted E olefin, and 12 or 13 stereocenters, making their synthesis extremely challenging. We now report our high yielding and highly stereoselective synthesis of the C1-C11 fragment common to both tedanolide and 13-deoxytedanolide using the first practical synthetic application of the highly efficient nonaldol aldol methodolgy recently developed in our laboratories.4 Using the nonaldol aldol transformation, it is possible to obtain highly enantioand diastereospecific propionate units 6 via the Lewis acid (4) (a) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208 and references therein. (b) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1995, 117, 7379. (c) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1997, 119, 12150. (d) D’Amico, D. C. Ph.D. Thesis, UCLA, 1995. (e) Jung, M. E.; Lee, W. S.; Sun, D. Org. Lett. 1999, 1, 307. (f) Jung, M. E.; Sun, D. Tetrahedron Lett. 1999, 40, 8343.
catalyzed rearrangement of chiral epoxy alcohols 5 without the use of chiral auxiliaries in the key step (obviously the step that produces the epoxy alcohols uses chiral reagents). Our convergent retrosynthetic analysis for the synthesis of both tedanolide and 13-deoxytedanolide called for the cleavage of the macrocyclic ring at the C1-C17 ester functionality and the C12-C13 bond, generating the C1-C12 fragment 3 and the C13-C24 fragment 4 (Scheme 1).
Scheme 1
Wittig olefination,5 and 1,2-reduction proceeded in good yield to produce the desired allylic alcohol 9. TBS protection of alcohol 9 followed by DMTr group removal afforded the desired homoallylic alcohol 10 in excellent yield. NBSpromoted cyclization6 of the free homoallylic alcohol onto the double bond generated the bromotetrahydrofuran 11 in good yield as a single diastereomer with the stereochemistry proven by NOE analysis. Our decision to proceed via the bromotetrahydrofuran functionality was based on previous results,7 which demonstrated the utility of this protecting group as a masked homoallylic methyl ketone. Deprotection of the TBS ether 11, followed by Swern oxidation and Wittig olefination, produced the desired E-conjugated ester 12 in good yield over three steps (Scheme 3). 1,2-Reduction of conjugated ester 12 afforded the
Scheme 3
The synthesis of the top fragment 3 began with commercially available methyl R (-)-3-hydroxy-2-methylpropionate 7 (Scheme 2), which was protected with a dimethox-
Scheme 2
ytrityl group (DMTr) and reduced to afford the monoprotected diol 8 in quantitative yield. Swern oxidation, followed by 1670
expected allylic alcohol 13 in high yield as a single product. With the allylic alcohol 13 in hand, we attempted to take advantage of the stereochemical information present in the bromotetrahydrofuran ring to influence the stereochemical outcome of the epoxidation. Unfortunately, all of the substrate-controlled epoxidation conditions attempted yielded the undesired epoxide 14 as the major product. However, the use of Sharpless asymmetric epoxidation conditions8 provided a 10:1 mixture of epoxides 14 and 15 with the desired epoxide 15 being the major diastereomer. (5) Fleck, F.; Schinz, H. HelV. Chim. Acta 1950, 33, 146. (6) (a) Parker, K. A.; O’Fee, R. J. Am. Chem. Soc. 1983, 105, 654. (b) Rychnovsky, S. D.; Barlett, P. A. J. Am. Chem. Soc. 1981, 103, 3963. (c) Mihailovic, M. Lj.; Marinkovic, D. J. Serb. Chem. Soc. 1985, 50, 5. (d) Harding, K. E.; Tiner, T. H. Electrophilic Heteroatom Cyclizations. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. IV, p 363. (7) Jung, M. E.; Karama, U.; Marquez, R. J. Org. Chem. 1999, 64, 663. (8) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136. (b) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. (c) Rossitier, B. E.; Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 464. (d) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237. Org. Lett., Vol. 2, No. 12, 2000
Crucial nonaldol aldol rearrangement of epoxide 15 provided the pivotal aldehyde aldol product 16 as a single diastereomer in excellent yield and without any need for purification (Scheme 4). The stereochemistry of the aldehyde
steps. Epoxidation of alcohol 20 under substrate-controlled conditions yielded, after silylation of the free hydroxyl, the desired epoxide 21 in 65% yield. Once the desired epoxide 21 was in hand, the final nonaldol aldol rearrangement required to complete the C1C11 fragment of tedanolide was carried out (Scheme 6).
Scheme 4 Scheme 6
16 was confirmed via NOE and J-value analysis of the acetonide derivative 17 which was readily prepared in three steps from aldehyde 16 (Scheme 4). Wittig olefination of aldehyde 16 proceeded in excellent yield and with complete stereoselectivity to produce the E-conjugated ester 18 (Scheme 5). 1,2-Reduction, followed
Scheme 5
by deprotection of the secondary silyl group and subsequent protection of the primary alcohol of the resulting diol, afforded the desired secondary alcohol intermediate 19 in good yield over three steps. Mesylation of the free secondary hydroxyl group followed by silyl group removal produced the required allylic alcohol 20 in excellent yield over both Org. Lett., Vol. 2, No. 12, 2000
Treatment of epoxide 21 with trimethylsilyl triflate, followed by Still-Wittig olefination conditions9,10 afforded the desired C1-C11 Z-conjugated ester 22 in 80% yield as a 1:1 mixture with the pyran derivative 23. Formation of the pyran side-product 23 was rationalized as originating from the attack of the tetrahydrofuran oxygen on the tertiary carbon of the activated epoxide 24 to generate the bicyclic intermediate 25. Intermediate 25 is then hydrolyzed during aqueous workup to give the observed pyran 23 (Scheme 7).
Scheme 7
In conclusion, we have demonstrated the feasibility of using the nonaldol aldol methodology toward an efficient synthesis of tedanolide 1 and 13-deoxytedanolide 2. With its ease of use, no purification requirements and no need for expensive chiral auxiliaries, we have shown that the nonaldol aldol methodology is a viable and economic alternative to (9) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. (10) We find that it is often advantageous to use the aldehydes immediately upon their formation rather than to isolate and try to purify them since one often observes some decomposition upon purification. 1671
traditional asymmetric aldol methods. Further developments in our approach toward the total synthesis of tedanolide and 13-deoxytedanolide will be published in due course. Acknowledgment. We thank the National Institutes of Health (CA-72684) for generous financial support. R.M. would like to thank the University of California President’s Office for a fellowship.
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Supporting Information Available: The NMR data and experimental procedures for compounds 8-23 are available as Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org.
OL005675L
Org. Lett., Vol. 2, No. 12, 2000
